Prognostic Factors for Survival After Transarterial Chemoembolization Combined with Sorafenib in the Treatment of BCLC Stage B and C Hepatocellular Carcinomas

Rationale and Objective

The objective of this study was to analyze prognostic factors for survival after transarterial chemoembolization (TACE) combined with sorafenib for hepatocellular carcinoma (HCC) of Barcelona Clinic Liver Cancer (BCLC) stages B and C.

Materials and Methods

Clinical data of 198 patients with BCLC stage B and C HCCs who underwent TACE combined with sorafenib between June 2012 and January 2017 were retrospectively collected and analyzed. Survival curves were detected using log-rank test. Univariate analysis was performed using log-rank test with respect to 11 prognostic factors potentially affecting survival. All statistically significant prognostic factors identified by univariate analysis were entered into a Cox proportion hazards regression model to identify independent predictors of survival. P values were two-sided and P < 0.05 was considered statistically significant.

Results

By the end of this study, the median follow-up duration was 43.6 months. The median overall survival (OS) of the patients was 21.0 months (95% confidence interval [CI]: 16.94–25.05), and the 1-, 2-, 3- and 5-year OS rates were 72%, 43%, 28%, and 4%, respectively. Tumor size (χ 2 = 33.607, P < 0.0001), tumor number (χ 2 = 4.084, P = 0.043), Child-Pugh class (χ 2 = 33.187, P < 0.0001), BCLC stage (χ 2 = 50.224, P < 0.0001), portal vein tumor thrombus (χ 2 = 88.905, P < 0.0001), Eastern Cooperative Oncology Group (ECOG) performance status (χ 2 = 98.007, P < 0.0001), extrahepatic spread (χ 2 = 34.980, P < 0.0001), TACE times (χ 2 = 8.350, P = 0.015), and sorafenib treatment strategy (χ 2 = 81.593, P < 0.0001) were found to be significantly associated with OS by univariate analysis. Multivariate analysis showed that BCLC stage (95% CI: 1.133–3.982, P = 0.019), extrahepatic spread (95% CI: 1.136–2.774, P = 0.012), and sorafenib treatment duration (95% CI: 0.352–0.574, P = 0.000) were independent prognostic factors associated with OS. There were no serious treatment-related adverse events.

Conclusions

This study showed that extrahepatic spread was a risk factor, and sorafenib treatment and superior BCLC stage were protective factors. Therefore, the study indicated that TACE combined with sorafenib was an effective and safe treatment for patients with BCLC stage B HCC without extrahepatic spread.

Introduction

Hepatocellular carcinoma (HCC) is one of the most common malignances. HCC is the third leading causes of cancer mortality worldwide. More than 700,000 new cases are diagnosed as HCC annually and its incidence is increasing in Asia as well as in the rest of the world . Nowadays, surgical resection and liver transplantation are still considered as the first-line treatments for patients with very early- or early-stage HCC . However, HCC is a highly aggressive liver neoplasm; the majority of patients were diagnosed at the intermediate and advanced stages of tumor growth. The Barcelona Clinic Liver Cancer (BCLC) staging system has been widely accepted as an offer treatment guideline that comprehensively considers the performance status of patients, hepatic function, tumor number, and tumor size. The BCLC staging system has been endorsed by the European Association for the Study of Liver Disease and the American Association for the Study of Liver Disease (AASLD) .

According to the BCLC staging system, transarterial chemoembolization (TACE) and sorafenib have been recommended as the standard therapies for patients with HCC of BCLC stages B and C, respectively . Sorafenib is a kind of oral multikinase inhibitor with antiproliferative and antiangiogenic effects by blocking the RAF-MEK-ERK signal transduction pathway . Theoretically, sorafenib was believed to decrease the angiogenesis of solid tumor by inhibiting the expression level of vascular endothelial growth factor (VEGF) after TACE treatment . Hence, sorafenib was expected to improve the clinical efficacy of TACE by decreasing post-TACE angiogenesis in the treatment of HCC. Portal vein tumor thrombus (PVTT) is an important leading cause of BCLC stage C HCC-related deaths. Usually, PVTT can be a cause of tumor spreading, failure of liver function, and portal vein hypertension, which lead to complicated ascites and variceal rupture. According to the available clinical guidelines, sorafenib has been widely recommended as the standard therapy for HCC with PVTT. In recent years, several studies had considered TACE as a palliative treatment choice for patients with BCLC stage C HCC . Pan et al., Liu et al., and Liu et al. had reported that TACE was safe and effective in the treatment of advanced HCC with PVTT . In Asia, the BCLC stage C HCC is suggested to be an indication for TACE treatment, and an increasing number of clinical trials in the field of combined sorafenib and TACE treatment of HCC are taking place .

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Materials and Methods

Study Population

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Combined TACE-Sorafenib Therapy

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Treatment Efficacy and Toxicity Evaluation

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Follow-up

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Statistical Analysis

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Results

Patients

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TABLE 1

Baseline Characteristics of the Included Patients in This Study

Variables No. of Patients (%) Age (y) ≤40 40 (20.2) 41~60 111 (56.1) >60 47 (23.7) Gender Male 174 (87.9) Female 24 (12.1) BCLC stage B 53 (26.8) C 145 (73.2) Tumor size Small HCC (TS ≤ 3 cm) 11 (5.6) Nodular type (3 cm < TS ≤ 5 cm) 27 (13.6) Massive type (5 cm < TS ≤ 10 cm) 87 (43.9) Huge type (10 cm < TS) 73 (36.9) Tumor number Single 65 (32.8) Multiple 133 (67.2) Child-Pugh class A 150 (75.8) B 48 (24.2) ECOG score 0 71 (35.9) 1 73 (36.9) 2 54 (27.2) PVTT None 112 (56.5) Branch type 57 (28.9) Trunk type 29 (14.6) AFP (ng/mL) <200 94 (47.5) ≥200 104 (52.5) Biopsy High differentiation 77 (61.6) Low differentiation 48 (38.4) Liver cirrhosis Yes 192 (96.9) Unknown 6 (3.1) Hepatitis Without 10 (5.1) With 188 (94.9) Extrahepatic spread Without 157 (79.3) With 41 (20.7) TACE times Once 42 (21.2) Twice 50 (25.3) ≥Triple 106 (53.5) Sorafenib (mo) <6 48 (24.2) 6–12 71 (35.9) >12 79 (39.9)

AFP, alpha fetal protein; BCLC, Barcelona Clinic Liver Cancer; ECOG, Eastern Cooperative Oncology Group; HCC, hepatocellular carcinoma; PVTT, portal vein tumor thrombus; TACE, transarterial chemoembolization.

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Treatment Efficacy

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TABLE 2

Prognostic Factors for Survival by Univariate Analysis

Variables No. of Patients Overall Survival Rate Median Survival Time (mo) (95% Confidence Interval) χ 2 P 1 y 2 y 3 y 5 y Tumor size (cm) 33.607 <0.001 Small HCC (≤3) 11 0.91 0.70 0.54 0.32 40 (22.30–57.70) Nodular type (3–5) 27 0.93 0.73 0.42 0.06 35 (28.55–41.45) Massive type (5–10) 87 0.75 0.43 0.39 0.05 22 (18.16–25.84) Huge type (>10) 73 0.58 0.25 0.04 0.00 13 (11.73–14.27) Tumor number 4.084 0.043 Single 65 0.84 0.51 0.35 0.05 27 (22.48–31.52) Multiple 133 0.66 0.38 0.25 0.04 17 (13.32–20.68) PVTT 88.905 <0.001 None 112 0.88 0.58 0.42 0.07 32 (25.09–38.91) Branch 57 0.67 0.36 0.18 0.00 14 (8.39–19.61) Trunk 29 0.24 0.00 0.00 0.00 9 (4.78–13.22) BCLC stage 50.224 <0.001 B 53 0.94 0.87 0.65 0.13 42 (37.65–46.35) C 145 0.64 0.27 0.15 0.00 14 (12.72–15.27) ECOG score 98.007 <0.001 0 71 0.97 0.72 0.55 0.09 39 (34.29–43.71) 1 73 0.74 0.41 0.18 0.00 19 (11.04–26.96) 2 54 0.37 0.06 0.06 0.00 10 (7.06–12.93) Child-Pugh class 33.187 <0.001 A 150 080 0.51 0.35 0.06 27 (19.27–34.74) B 48 0.46 0.16 0.07 0.00 11 (7.01–14.99) Extrahepatic spread 34.980 <0.001 Without 157 0.78 0.51 0.35 0.05 27 (21.12–32.88) With 41 0.49 0.08 0.00 0.00 10 (4.16–15.84) TACE times 8.350 0.015 Once 42 0.51 0.30 0.26 0.00 12 (9.39–14.61) Twice 50 0.65 0.37 0.25 0.13 17 (11.13–22.87) ≥Triple 106 0.84 0.50 0.32 0.05 25 (21.16–28.84) Sorafenib (mo) 81.593 <0.001 <6 48 0.39 0.16 0.05 0.00 8 (6.37–9.64) 6–12 71 0.62 0.20 0.12 0.00 14 (13.03–14.97) >12 79 0.99 0.73 0.51 0.09 37 (33.07–40.93)

BCLC, Barcelona Clinic Liver Cancer; ECOG, Eastern Cooperative Oncology Group; HCC, hepatocellular carcinoma; PVTT, portal vein tumor thrombus; TACE, transarterial chemoembolization.

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